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New Bradykinin Analogues Modified in Position 6 and 7 with Naphthylalanine

Prahl A., Derdowska I., Dawidowska O., Neubert K., Hartrodt B., Wierzba T., Juzwa W., Lammek B.

Polish Journal of Chemistry

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2003

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Vol. 77 / nr 7

881-887

EN

We describe the synthesis and some pharmacological properties of eight new analogues of a previously synthesized bradykinin antagonist, D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser- D-Phe-Thi-Arg. Two peptides were designed by substitution of Ser6 with L-1- and L-2-naphthylalanine. In two further analogues this modification was combined with placement in position 7 of D-naphthylalanine residue. We also obtained four analogues by acylation of N-terminus of the peptides mentioned above with 1-adamantaneacetic acid. The activity of analogues was assessed by their ability to inhibit vasodepressor response to exogenous bradykinin (rat blood pressure test). Our results indicate that the modifications proposed decreased significantly the B2 antagonistic activity. Moreover, our earlier observation, suggesting that acylation of the N-terminus of many BK antagonists with bulky groups consistently improved the antagonistic potency, appears to be valid only for one pair of analogues.

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New bradykinin Analogues Substituted in Positions 6 and 7 with Enantiomers of N-Methylphenylalanine

Wierzba T., Derdowska I., Juzwa W., Neubert K., Hartrodt B., Lammek B.

Polish Journal of Chemistry

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2002

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Vol. 76 / nr 5

713-719

EN

Four new analogues of a previously designed bradykinin antagonist, D-Arg-Arg-Pro- -Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg, containing replacements in positions 6 and 7 with all possible combinations of enantiomers of N-methylphenylalanine (MePhe) were designed, synthesized and bioassayed. The presence of two consecutive MePhe residues in the sequence of the analogues caused great difficulties in the synthesis. The best results for the CO-N(CH3) bond formation were obtained using O-(7-azabenzotriazol-1-yl)-1,1,3,3- -tetramethyluronium hexafluorophosphate/7-azabenzotriazol-1-ol (HATU/HOAt) as coupling reagent (Fmoc strategy). The antagonistic potency of these peptides was assessed by their ability to inhibit vasodepressor response to exogenous bradykinin in conscious rats. Our results showed that the modifications proposed resulted in a decrease in antagonistic activity. However, we demonstrated once again that the D-amino acid in position 7 ofBKantagonists may be replaced by a suitable L-amino acid residue. Our results may be of value in the design of new B2-antagonists.

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New Analogues of Bradykinin Substituted in the C-Terminal Part of the Molecule with Naphthylalanine

Prahl A., Derdowska I., Dawidowska O., Neubert K., Hartrodt B., Wierzba T., Juzwa W., Lammek B.

Polish Journal of Chemistry

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2002

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Vol. 76 / nr 10

1433-1439

EN

This paper describes the synthesis and some pharmacological properties of eight new analogues of a previously synthesized bradykinin antagonist, D-Arg-Arg-Pro-Hyp-Gly- Thi-Ser-D-Phe-Thi-Arg. Two peptides were designed by substitution of Thi8 with L-1- and L-2-naphthylalanine. In two further analogues this modification was combined with placement in position 7 of D-2-naphthylalanine residue. Finally, we obtained four analogues by acylation of N-terminus of the peptides mentioned above with 1-adamantaneacetic acid. The activity of analogues was assessed by their ability to inhibit vasodepressor response to exogenous bradykinin (rat blood pressure test). Our results indicate that the modification proposed decreased the B2 antagonistic activity, however, the range of this effect was different. We also observed that even minor changes in the structure of the C-terminal part of the B2 antagonists may significantly influence their activity.